The acetylcholinesterase inhibitors (AchEI) are currently the most broadly used drugs to treat AIzheirmer's disease (AD). Unfortunately none of the beneficial effect lasts for more than a short two years time period, probably due to the progressive degeneration of the cholinergic neurons. This indicates that aiming at the same time at another target distinct to the cholinergic pathway might be a resourceful strategy to treat AD. Our long-term goal is to develop a drug (SP004), which inhibits AchE and at the same time releases an active metabolite (SP004m), which targets the sigma-1 receptor. Our main hypothesis is that the memory improvement and the anti-depressant effects triggered by the sigma-1 receptor activation will potentiate the cognitive effects induced by the inhibition of AchE. This hypothesis is based on the observations that sigma- 1 agonists (1) improve memory impairment in rats and mice, (2) display anti-depressant effects on rats submitted to the forced swimming test, (3) increase the Ach release in rats brain, (4) rescue neuronal cells against excitotoxicity, which contributes the to preservation of the cholinergic neurons necessary to a longlasting improvement of the patient's condition. Our specific aims are to: (1) Characterize the Ache inhibitory effect of SP004 in vivo by monitoring the cerebral Ach concentrations in rats injected with SP004, ex vivo by measuring the Ache activity on rats brain structures from rats injected with SP004 and in vitro on the human recombinant enzyme. (2) Characterize the sigma-1 ligand properties of SP004 and SP004m. Kd and nH will be determined on sigma-1 recombinant human receptor and on different rat brain sub-cellular fractions. The effect of SP004m on Ach release will be monitored in vivo using cerebral microdialysis on rats. (3) Assess the effect of SP004 and SP004m on a scopolamine-induced memory impairment rat model and on a forced swimming test. Our goal in this Phase I STTR application is to prove the concept that a dual activity compound, such as SP004, is efficacious in an in vivo settings simulating human neuropathology. [unreadable] [unreadable] [unreadable]